| AMERICAN DRUGS | ANATOMY | HEALTH TOPICS | HIV/AIDS GLOSSARY | DISEASES | HEALTH ARTICLES | GENOME | OCCUPATIONS |

Velmetia

Spanish Simplified Chinese French German Russian Hindi Arabic Portuguese
















Summary for the public


What is Velmetia?

Velmetia is a medicine that contains two active substances, sitagliptin and metformin hydrochloride. It is available as capsule-shaped tablets (pink: 50 mg sitagliptin and 850 mg metformin hydrochloride; red: 50 mg sitagliptin and 1,000 mg metformin hydrochloride).


What is Velmetia used for?

Velmetia is used in patients with type 2 diabetes to improve the control of blood glucose (sugar) levels. It is used in addition to diet and exercise in the following ways: 

  • in patients who are not satisfactorily controlled on metformin (an antidiabetes medicine) used on its own;
  • in patients who are already taking a combination of sitagliptin and metformin as separate tablets;
  • in combination with a sulphonylurea, a PPAR-gamma agonist such as a thiazolidinedione, or insulin (other types of antidiabetes medicine) in patients who are not satisfactorily controlled on this medicine and metformin.

The medicine can only be obtained with a prescription.


How is Velmetia used?

Velmetia is taken twice a day. The strength of tablet to use depends on the dose of the other antidiabetes medicines that the patient was taking before. If Velmetia is taken with a sulphonylurea or insulin, the dose of the sulphonylurea or insulin may need to be lowered, to avoid hypoglycaemia (low blood sugar levels).

The maximum dose of sitagliptin is 100 mg a day. Velmetia should be taken with food to avoid any stomach problems caused by metformin.


How does Velmetia work?

Type 2 diabetes is a disease in which the pancreas does not make enough insulin to control the level of glucose in the blood or when the body is unable to use insulin effectively. The active substances in Velmetia, sitagliptin and metformin hydrochloride, each have a different mode of action.

Sitagliptin is a dipeptidyl-peptidase-4 (DPP-4) inhibitor. It works by blocking the breakdown of ‘incretin’ hormones in the body. These hormones are released after a meal and stimulate the pancreas to produce insulin. By increasing the levels of incretin hormones in the blood, sitagliptin stimulates the pancreas to produce more insulin when blood glucose levels are high. Sitagliptin does not work when the blood glucose is low. Sitagliptin also reduces the amount of glucose made by the liver, by increasing insulin levels and decreasing the levels of the hormone glucagon. Sitagliptin has been authorised in the European Union (EU) as Januvia and Xelevia since 2007, and as Tesavel since 2008.

Metformin works mainly by inhibiting glucose production and reducing its absorption in the gut. Metformin has been available in the EU since the 1950s.

As a result of the action of both active substances, blood glucose levels are reduced and this helps to control type 2 diabetes.


How has Velmetia been studied?

Sitagliptin on its own as Januvia/Xelevia/Tesavel can be used with metformin, and with both metformin and a sulphonylurea, in type 2 diabetes patients. The company presented the results of three studies of Januvia/Xelevia to support the use of Velmetia in patients who were not satisfactorily controlled on their existing metformin treatment.

Two of the studies looked at sitagliptin as an add-on to metformin: the first compared it with placebo (a dummy treatment) in 701 patients, and the second compared it with glipizide (a sulphonylurea) in 1,172 patients. The third study compared sitagliptin with placebo, when used as an add-on to glimepiride (another sulphonylurea), with or without metformin, in 441 patients. The results of three further studies were used to support the use of Velmetia. The first included 1,091 patients who were not satisfactorily controlled on diet and exercise alone and compared the effect of Velmetia with that of metformin or sitagliptin alone. The second included 278 patients who were not satisfactorily controlled on the combination of metformin and rosiglitazone (a PPAR-gamma agonist) and compared the effects of adding sitagliptin or placebo. The third included 641 patients who were not satisfactorily controlled on a stable dose of insulin, three-quarters of whom were also taking metformin. This study also compared the effects of adding sitagliptin or placebo.

In all of the studies, the main measure of effectiveness was the change in the levels of a substance in the blood called glycosylated haemoglobin (HbA1c), which gives an indication of how well the blood glucose is controlled.

The company carried out additional studies to show that the active substances in Velmetia are absorbed by the body in the same way as the two medicines given separately.


What benefit has Velmetia shown during the studies?

Velmetia was more effective than metformin alone. Adding 100 mg sitagliptin to metformin reduced HbA1c levels by 0.67% (from around 8.0%) after 24 weeks, compared with a fall of 0.02% in the patients adding placebo. The effectiveness of adding sitagliptin to metformin was similar to that of adding glipizide. In the study in which sitagliptin was added to glimepiride and metformin, the levels of HbA1c were reduced by 0.59% after 24 weeks, compared with an increase of 0.30% in the patients adding placebo.

In the first of the three further studies, Velmetia was more effective than metformin or sitagliptin alone. In the second, HbA1c levels were reduced by 1.03% after 18 weeks in patients adding sitagliptin to metformin and rosiglitazone, compared with a fall of 0.31% in those adding placebo.

Finally, they were reduced by 0.59% after 24 weeks in patients adding sitagliptin to insulin, compared with a fall of 0.03% in those adding placebo. There was no difference in this effect between the patients also taking metformin and those not taking it.


What is the risk associated with Velmetia?

The most common side effect with Velmetia (seen in between 1 and 10 patients in 100) is nausea (feeling sick). For the full list of all side effects reported with Velmetia, see the Package Leaflet.

Velmetia should not be used in people who may be hypersensitive (allergic) to sitagliptin, metformin or any of the other ingredients. It must not be used in patients who have diabetic ketoacidosis or pre-coma (dangerous conditions that can occur in diabetes), problems with the kidneys or liver, conditions that may affect the kidneys, or a disease that causes a reduced supply of oxygen to the tissues such as failure of the heart or lungs or a recent heart attack. It must also not be used in patients who consume excessive amounts of alcohol or who are alcoholic, or in women who are breast-feeding. For the full list of restrictions, see the Package Leaflet.


Why has Velmetia been approved?

The Committee for Medicinal Products for Human Use (CHMP) decided that Velmetia’s benefits are greater than its risks and recommended that it be given marketing authorisation.


Other information about Velmetia

The European Commission granted a marketing authorisation valid throughout the EU for Velmetia to Merck Sharp & Dohme Ltd on 16 July 2008. The marketing authorisation is valid for five years, after which it can be renewed.

Authorisation details
Name: Velmetia
EMEA Product number: EMEA/H/C/000862
Active substance: sitagliptin / metformin hydrochloride
INN or common name: sitagliptin / metformin
Therapeutic area: Diabetes Mellitus, Type 2
ATC Code: A10BD07
Marketing Authorisation Holder: Merck Sharp & Dohme Ltd.
Revision: 9
Date of issue of Market Authorisation valid throughout the European Union: 16/07/2008
Contact address:
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom



Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/850 mg film-coated tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 850 mg of metformin
hydrochloride.
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Capsule-shaped, pink film-coated tablet with “515” debossed on one side.
4.
CLINICAL PARTICULARS
4.1 Therapeutic indications
For patients with type 2 diabetes mellitus:
Velmetia is indicated as an adjunct to diet and exercise to improve glycaemic control in patients
inadequately controlled on their maximal tolerated dose of metformin alone or those already being
treated with the combination of sitagliptin and metformin.
Velmetia is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an
adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of
metformin and a sulphonylurea.
Velmetia is indicated as triple combination therapy with a peroxisome proliferator-activated receptor
gamma (PPARγ) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients
inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.
Velmetia is also indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to diet
and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone
do not provide adequate glycaemic control.
4.2 Posology and method of administration
Posology
The dose of antihyperglycaemic therapy with Velmetia should be individualised on the basis of the
patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum
recommended daily dose of 100 mg sitagliptin.
For patients inadequately controlled on maximal tolerated dose of metformin monotherapy
For patients not adequately controlled on metformin alone, the usual starting dose of Velmetia should
provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin
already being taken.
For patients switching from co-administration of sitagliptin and metformin
For patients switching from co-administration of sitagliptin and metformin, Velmetia should be
initiated at the dose of sitagliptin and metformin already being taken.
2
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of
metformin and a sulphonylurea
The dose of Velmetia should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose)
and a dose of metformin similar to the dose already being taken. When Velmetia is used in
combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the
risk of hypoglycaemia (see section 4.4).
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of
metformin and a PPARγ agonist
The dose of Velmetia should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose)
and a dose of metformin similar to the dose already being taken.
For patients inadequately controlled on dual combination therapy with insulin and the maximal
tolerated dose of metformin
The dose of Velmetia should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose)
and a dose of metformin similar to the dose already being taken. When Velmetia is used in
combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia
(see section 4.4).
For the different doses on metformin, Velmetia is available in strengths of 50 mg sitagliptin and
850 mg metformin hydrochloride or 1,000 mg metformin hydrochloride.
All patients should continue their diet with an adequate distribution of carbohydrate intake during the
day. Overweight patients should continue their energy-restricted diet.
Special populations
Renal impairment
Velmetia should not be used in patients with moderate or severe renal impairment (creatinine
clearance < 60 ml/min) (see sections 4.3 and 4.4).
Hepatic impairment
Velmetia should not be used in patients with hepatic impairment (see sections 4.3 and 5.2).
Elderly
As metformin and sitagliptin are excreted by the kidney, Velmetia should be used with caution as age
increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic
acidosis, particularly in the elderly (see sections 4.3 and 4.4). Limited safety data on sitagliptin is
available in patients > 75 years of age and care should be exercised.
Paediatric population
Velmetia is not recommended for use in children below 18 years of age due to a lack of data on its
safety and efficacy in this population.
Method of administration
Velmetia should be given twice daily with meals to reduce the gastrointestinal undesirable effects
associated with metformin.
4.3 Contraindications
Velmetia is contraindicated in patients with:
-
hypersensitivity to the active substances or to any of the excipients (see sections 4.4 and 4.8);
-
diabetic ketoacidosis, diabetic pre-coma;
-
acute conditions with the potential to alter renal function such as:
-
dehydration,
3
-
moderate and severe renal impairment (creatinine clearance < 60 ml/min) (see section 4.4);
-
severe infection,
-
intravascular administration of iodinated contrast agents (see section 4.4);
-
acute or chronic disease which may cause tissue hypoxia such as:
-
cardiac or respiratory failure,
-
recent myocardial infarction,
-
shock;
-
hepatic impairment;
-
acute alcohol intoxication, alcoholism;
-
lactation.
4.4 Special warnings and precautions for use
General
Velmetia should not be used in patients with type 1 diabetes and must not be used for the treatment of
diabetic ketoacidosis.
Pancreatitis
In post-marketing experience there have been spontaneously reported adverse reactions of acute
pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis:
persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation
of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or
haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Velmetia and
other potentially suspect medicinal products should be discontinued.
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment),
metabolic complication that can occur due to metformin accumulation. Reported cases of lactic
acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal
failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated
risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake,
hepatic insufficiency and any conditions associated with hypoxia.
Diagnosis
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l,
and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment
with the medicinal product should be discontinued and the patient hospitalised immediately (see
section 4.9).
Renal function
Metformin and sitagliptin are known to be substantially excreted by the kidney. Metformin-related
lactic acidosis increases with the degree of impairment of renal function, therefore, serum creatinine
concentrations should be determined regularly:
-
at least once a year in patients with normal renal function
-
at least two to four times a year in patients with serum creatinine levels at or above the upper
limit of normal and in elderly patients.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory
drug (NSAID).
Hypoglycaemia
Patients receiving Velmetia in combination with a sulphonylurea or with insulin may be at risk for
hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary.
4
-
shock,
Hypersensitivity reactions
Postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have
been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions
including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after
initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue Velmetia, assess for other potential causes of the
event, and institute alternative treatment for diabetes (see section 4.8).
Surgery
As Velmetia contains metformin hydrochloride, the treatment should be discontinued 48 hours before
elective surgery with general, spinal or epidural anaesthesia. Velmetia should not usually be resumed
earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be
normal.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure which has been associated with lactic acidosis in patients receiving metformin. Therefore,
Velmetia should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours
afterwards, and only after renal function has been re-evaluated and found to be normal (see
section 4.5).
Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously well controlled on Velmetia who develops laboratory
abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated
promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes
and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If
acidosis of either form occurs, Velmetia must be stopped immediately and other appropriate corrective
measures initiated.
4.5 Interaction with other medicinal products and other forms of interaction
Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1,000 mg twice
daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients
with type 2 diabetes.
Pharmacokinetic drug interaction studies with Velmetia have not been performed; however, such
studies have been conducted with the individual active substances of Velmetia, sitagliptin and
metformin.
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Velmetia (see
section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Cationic agents that are eliminated by renal tubular secretion (e.g., cimetidine) may interact with
metformin by competing for common renal tubular transport systems. A study conducted in seven
normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased
metformin systemic exposure (AUC) by 50 % and C max by 81 %. Therefore, close monitoring of
glycaemic control, dose adjustment within the recommended posology and changes in diabetic
treatment should be considered when cationic agents that are eliminated by renal tubular secretion are
co-administered.
The intravascular administration of iodinated contrast agents in radiological studies may lead to renal
failure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, Velmetia should
be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and
only after renal function has been re-evaluated and found to be normal (see section 4.4).
5
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring
performed, especially at the beginning of treatment with such medicinal products. If necessary, the
dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other
medicinal product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions following
co-administration of other medicinal products is low.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of
p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose
of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and C max of sitagliptin by
approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not
considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin
is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism,
including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a
more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-
stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.,
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in
patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting
of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion
transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid,
although the risk of clinically meaningful interactions is considered to be low. Concomitant
administration of OAT3 inhibitors has not been evaluated in vivo .
Effects of sitagliptin on other medicinal products
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical
studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide,
simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low
propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic
cationic transporter (OCT). Sitagliptin had a small effect on plasma digoxin concentrations, and may
be a mild inhibitor of p-glycoprotein in vivo .
Digoxin : Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of
0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of
digoxin was increased on average by 11 %, and the plasma C max on average by 18 %. No dose
adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be
monitored for this when sitagliptin and digoxin are administered concomitantly.
4.6 Fertility, pregnancy and lactation
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have
shown reproductive toxicity at high doses of sitagliptin (see section 5.3).
A limited amount of data suggest the use of metformin in pregnant women is not associated with an
increased risk of congenital malformations. Animal studies with metformin do not indicate harmful
6
effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal
development (see also section 5.3).
Velmetia should not be used during pregnancy. If a patient wishes to become pregnant or if a
pregnancy occurs, treatment with Velmetia should be discontinued and switched to insulin treatment
as soon as possible.
No studies in lactating animals have been conducted with the combined active substances of Velmetia.
In studies performed with the individual active substances, both sitagliptin and metformin are excreted
in the milk of lactating rats. Metformin is excreted in human milk in small amounts. It is not known
whether sitagliptin is excreted in human milk. Velmetia must therefore not be used in women who are
breast-feeding (see section 4.3).
4.7 Effects on ability to drive and use machines
Velmetia has no known influence on the ability to drive and use machines. However, when driving or
operating machines, it should be taken into account that dizziness and somnolence have been reported
with sitagliptin.
In addition, patients should be alerted to the risk of hypoglycaemia when Velmetia is used in
combination with sulphonylurea agents or with insulin.
4.8 Undesirable effects
There have been no therapeutic clinical trials conducted with Velmetia tablets however bioequivalence
of Velmetia with co-administered sitagliptin and metformin has been demonstrated (see section 5.2).
Sitagliptin and metformin
Adverse reactions considered as drug related reported in excess (> 0.2 % and difference > 1 patient) of
placebo and in patients receiving sitagliptin in combination with metformin in double-blind studies are
listed below as MedDRA preferred term by system organ class and absolute frequency (Table 1).
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Adverse reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin with
Metformin 1
Sitagliptin with
Metformin and a
Sulphonylurea 2
Sitagliptin with
Metformin and
a PPARγ Agent
(rosiglitazone) 3
Sitagliptin with
Metformin and
Insulin 4
Time-point
24-week
24-week
18-week
24-week
Metabolism and nutrition disorders
hypoglycaemia *
Very common
Common
Very common
Nervous system disorders
headache
Common
Uncommon
somnolence
Uncommon
Gastrointestinal disorders
diarrhoea
Uncommon
Common
nausea
Common
constipation
Common
upper abdominal
pain
Uncommon
7
 
Adverse reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin with
Metformin 1
Sitagliptin with
Metformin and a
Sulphonylurea 2
Sitagliptin with
Metformin and
a PPARγ Agent
(rosiglitazone) 3
Sitagliptin with
Metformin and
Insulin 4
Time-point
24-week
24-week
18-week
24-week
vomiting
Common
dry mouth
Uncommon
General disorders and administration site conditions
peripheral oedema
Common
Investigations
blood glucose
decreased
Uncommon
* In clinical trials of sitagliptin as monotherapy and sitagliptin as part of combination therapy with
metformin or metformin and a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were
similar to rates in patients taking placebo.
Observed in the 54-week analysis.
1
In this placebo-controlled 24-week study of sitagliptin 100 mg once daily added to ongoing
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin added to ongoing metformin compared to treatment with placebo added to ongoing
metformin was 9.3 % and 10.1 %, respectively.
In an additional 1-year study of sitagliptin 100 mg once daily added to ongoing metformin, the
incidence of adverse reactions considered as drug-related in patients treated with sitagliptin added to
ongoing metformin compared to sulphonylurea added to ongoing metformin was 14.5 % and
30.3 %, respectively.
In pooled studies of up to 1 year in duration comparing sitagliptin added to ongoing metformin to a
sulphonylurea agent added to ongoing metformin, adverse reactions considered as drug-related
reported in patients treated with sitagliptin 100 mg occurring in excess (> 0.2 % and difference
> 1 patient) of that in patients receiving the sulphonylurea agent are as follows: anorexia
(Metabolism and nutritional disorders; frequency uncommon) and weight decreased (Investigations;
frequency uncommon).
2
In this 24-week placebo-controlled study of sitagliptin 100 mg once daily added to ongoing
combination treatment with glimepiride and metformin, the overall incidence of adverse reactions
considered as drug-related in patients treated with the addition of sitagliptin to the ongoing treatment
with glimepiride and metformin was 18.1 % compared to treatment with the addition of placebo to
the ongoing treatment with glimepiride and metformin which was 7.1 %.
3
In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin,
which continued through 54 weeks, the incidence of adverse reactions considered as drug-related in
patients treated with sitagliptin combination compared to treatment with the placebo combination
was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in the 54-week
analysis (frequency common) in patients treated with the sitagliptin combination occurring in excess
(> 0.2 % and difference > 1 patient) of that in patients treated with the placebo combination were:
headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper respiratory tract
infection.
4
In this 24-week placebo-controlled study of sitagliptin 100 mg once daily as add-on to insulin and
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin in combination with insulin/metformin compared to treatment with placebo in
combination with insulin/metformin was 16.2 % and 9.0 %, respectively.
8
 
In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice
daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1,000 mg), the overall incidence of adverse
reactions considered as drug-related in patients treated with the combination of sitagliptin and
metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall
incidence of adverse reactions considered as drug-related in patients treated with the combination of
sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than
sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to
gastrointestinal adverse reactions.
Additional information on the individual active substances of the fixed dose combination
Sitagliptin
In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily
alone compared to placebo, adverse reactions considered as drug-related reported in patients treated
with sitagliptin in excess (> 0.2 % and difference > 1 patient) of that in patients receiving placebo are
headache, hypoglycaemia, constipation, and dizziness.
In addition to the drug related adverse reactions described above, adverse events (reported regardless
of causal relationship to medicinal product) occurring in at least 5 % and more commonly in patients
treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional
adverse events that occurred more frequently in patients treated with sitagliptin (not reaching the 5 %
level, but occurring with an incidence of > 0.5 % higher with sitagliptin than that in the control group)
included osteoarthritis and pain in extremity.
Across clinical studies, a small increase in white blood cell (WBC) count (approximately
200 cells/microl difference in WBC vs placebo; mean baseline WBC approximately
6,600 cells/microl) was observed due to an increase in neutrophils. This observation was seen in most
but not all studies. This change in laboratory parameters is not considered to be clinically relevant.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed
with sitagliptin treatment.
Post-marketing data
During post-approval use of Velmetia or sitagliptin, one of the active substances of Velmetia,
additional adverse reactions have been reported (frequency not known). These reactions have been
reported when Velmetia or sitagliptin have been used alone and/or in combination with other
antihyperglycaemic agents: hypersensitivity reactions including anaphylaxis, angioedema, rash,
urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome
(see section 4.4); acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotizing
pancreatitis (see section 4.4); impaired renal function, including acute renal failure (sometimes
requiring dialysis); vomiting.
Metformin
Clinical Trial Data and Post-marketing data
Table 2 presents adverse reactions by system organ class and by frequency category. Frequency
categories are based on information available from metformin Summary of Product Characteristics
available in the EU.
9
Table 2. The frequency of metformin adverse reactions identified from clinical trial and
postmarketing data
Adverse reaction
Frequency
Metabolism and nutrition disorders
lactic acidosis Very rare
vitamin B12 deficiency a Very rare
Nervous system disorders
metallic taste Common
Gastrointestinal disorders
gastrointestinal symptoms b Very common
Hepatobiliary disorders
liver function disorders, hepatitis Very rare
Skin and subcutaneous tissue disorders
urticaria, erythema, pruritis Very rare
a Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption
which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic
anaemia).
b Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
occur most frequently during initiation of therapy and resolve spontaneously in most cases.
4.9 Overdose
No data are available with regard to overdose of Velmetia.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg
in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and
400 mg per day for periods of up to 28 days.
A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosis
which is a medical emergency and must be treated in hospital. The most effective method to remove
lactate and metformin is haemodialysis.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5 % of the dose was removed
over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically
appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an
electrocardiogram), and institute supportive therapy if required.
10
 
5.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicines used in diabetes, Combinations of oral blood glucose lowering
drugs, ATC code: A10BD07
Velmetia combines two antihyperglycaemic agents with complementary mechanisms of action to
improve glycaemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl
peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Sitagliptin
Sitagliptin phosphate is an orally-active, potent, and highly selective inhibitor of the dipeptidyl
peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class of
agents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels
of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the
physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or
elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also
lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.
When blood glucose levels are low, insulin release is not enhanced and glucagon secretion is not
suppressed. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not
inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in
chemical structure and pharmacological action from GLP-1 analogues, insulin, sulphonylureas or
meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-
glucosidase inhibitors, and amylin analogues.
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations,
whereas metformin alone increased active and total GLP-1 concentrations to similar extents.
Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
Sitagliptin, but not metformin, increased active GIP concentrations.
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination
treatment.
In clinical trials, sitagliptin as monotherapy improved glycaemic control with significant reductions in
haemoglobin A 1c (HbA 1c ) and fasting and postprandial glucose. Reduction in fasting plasma glucose
(FPG) was observed at 3 weeks, the first time point at which FPG was measured. The observed
incidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo. Body weight
did not increase from baseline with sitagliptin therapy. Improvements in surrogate markers of beta cell
function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and
measures of beta cell responsiveness from the frequently-sampled meal tolerance test were observed.
Studies of sitagliptin in combination with metformin
In a 24-week, placebo-controlled clinical study to evaluate the efficacy and safety of the addition of
sitagliptin 100 mg once daily to ongoing metformin, sitagliptin provided significant improvements in
glycaemic parameters compared with placebo. Change from baseline in body weight was similar for
patients treated with sitagliptin relative to placebo. In this study there was a similar incidence of
hypoglycaemia reported for patients treated with sitagliptin or placebo.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in
combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in
glycaemic parameters compared with either monotherapy. The decrease in body weight with the
combination of sitagliptin and metformin was similar to that observed with metformin alone or
placebo; there was no change from baseline for patients on sitagliptin alone. The incidence of
hypoglycaemia was similar across treatment groups.
11
Study of sitagliptin in combination with metformin and a sulphonylurea
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride (alone or in combination with metformin). The addition of
sitagliptin to glimepiride and metformin provided significant improvements in glycaemic parameters.
Patients treated with sitagliptin had a modest increase in body weight (+1.1 kg) compared to those
given placebo.
Study of sitagliptin in combination with metformin and a PPARγ agonist
A 54-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to the combination of rosiglitazone and metformin. The addition of
sitagliptin to rosiglitazone and metformin provided significant improvements in glycaemic parameters
at the primary timepoint of Week 18, with improvements sustained through the end of the study.
Change from baseline in body weight was similar for patients treated with sitagliptin relative to
placebo (1.9 vs. 1.3 kg).
Study of sitagliptin in combination with metformin and insulin
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin
(at least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In
patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day.
Data from the 73 % of patients who were taking metformin are presented in Table 3. The addition of
sitagliptin to insulin provided significant improvements in glycaemic parameters. There was no
meaningful change from baseline in body weight in either group.
Table 3: HbA 1c results in placebo-controlled combination therapy studies of sitagliptin and
metformin *
Study
Mean baseline
HbA 1c (%)
Mean change from
baseline HbA 1c (%)
Placebo-corrected mean change
in HbA 1c (%)
(95 % CI)
Sitagliptin 100 mg once daily
added to ongoing metformin
therapy
(N=453)
8.0
-0.7
-0.7 †‡
(-0.8, -0.5)
Sitagliptin 100 mg once daily
added to ongoing glimepiride
+ metformin therapy
(N=115)
8.3
-0.6
-0.9 †‡
(-1.1, -0.7)
Sitagliptin 100 mg once daily
added to ongoing
rosiglitazone + metformin
therapy (N=170)
-0.7 †‡
(-0.9, -0.5)
-0.8 †‡
(-1.0, -0.5)
Week 18
8.8
-1.0
Week 54
8.8
-1.0
Sitagliptin 100 mg once daily
added to ongoing insulin +
metformin therapy
(N=223)
8.7
-0.7 §
-0.5 §,‡
(-0.7, -0.4)
Initial Therapy (twice daily) :
Sitagliptin 50 mg +
metformin 500 mg
(N=183)
8.8
-1.4
-1.6 †‡
(-1.8, -1.3)
12
 
Study
Mean baseline
HbA 1c (%)
Mean change from
baseline HbA 1c (%)
Placebo-corrected mean change
in HbA 1c (%)
(95 % CI)
Initial Therapy (twice daily) :
Sitagliptin 50 mg +
metformin 1,000 mg
(N=178)
8.8
-1.9
-2.1 †‡
(-2.3, -1.8)
* All Patients Treated Population (an intention-to-treat analysis).
Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value.
p< 0.001 compared to placebo or placebo + combination treatment.
HbA 1c (%) at week 24.
§ Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and
baseline value.
In a 52-week study, comparing the efficacy and safety of the addition of sitagliptin 100 mg once daily
or glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin
monotherapy, sitagliptin was similar to glipizide in reducing HbA 1c (-0.7 % mean change from
baselines at week 52, with baseline HbA 1c of approximately 7.5 % in both groups). The mean glipizide
dose used in the comparator group was 10 mg per day with approximately 40 % of patients requiring a
glipizide dose of ≤ 5 mg/day throughout the study. However, more patients in the sitagliptin group
discontinued due to lack of efficacy than in the glipizide group. Patients treated with sitagliptin
exhibited a significant mean decrease from baseline in body weight (-1.5 kg) compared to a significant
weight gain in patients administered glipizide (+1.1 kg). In this study, the proinsulin to insulin ratio, a
marker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with
glipizide treatment. The incidence of hypoglycaemia in the sitagliptin group (4.9 %) was significantly
lower than that in the glipizide group (32.0 %).
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
-
by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
-
in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation
-
by delaying intestinal glucose absorption.
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin
increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and
GLUT-4).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term
clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with
metformin after failure of diet alone showed:
-
a significant reduction of the absolute risk of any diabetes-related complication in the metformin
group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups
(40.1 events/1,000 patient-years), p=0.0034
-
a significant reduction of the absolute risk of any diabetes-related mortality: metformin
7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
-
a significant reduction of the absolute risk of overall mortality: metformin
13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011),
and versus the combined sulphonylurea and insulin monotherapy groups
18.9 events/1,000 patient-years (p=0.021)
13
 
-
a significant reduction in the absolute risk of myocardial infarction: metformin
11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
The European Medicines Agency has waived the obligation to submit the results of studies with
Velmetia in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
Velmetia
A bioequivalence study in healthy subjects demonstrated that the Velmetia (sitagliptin/metformin
hydrochloride) combination tablets are bioequivalent to co-administration of sitagliptin phosphate and
metformin hydrochloride as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of
Velmetia.
Sitagliptin
Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,
with peak plasma concentrations (median T max ) occurring 1 to 4 hours post-dose, mean plasma AUC of
sitagliptin was 8.52 μM•hr, C max was 950 nM. The absolute bioavailability of sitagliptin is
approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the
pharmacokinetics, sitagliptin may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not
established for C max and C 24hr (C max increased in a greater than dose-proportional manner and C 24hr
increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of
sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound
to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [ 14 C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as
metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to
contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the
primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution
from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isoenzymes CYP3A4, 2C8, 2C9, 2D6,
1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
Following administration of an oral [ 14 C]sitagliptin dose to healthy subjects, approximately 100 % of
the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of
dosing. The apparent terminal t ½ following a 100-mg oral dose of sitagliptin was approximately
12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was
approximately 350 ml/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in
the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not
14
been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in
mediating the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not
reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2
transporters. In vitro , sitagliptin did not inhibit OAT3 (IC50=160 μM) or p-glycoprotein (up to
250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study
sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild
inhibitor of p-glycoprotein.
Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with
type 2 diabetes.
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of
sitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to normal
healthy control subjects. The study included patients with renal impairment classified on the basis of
creatinine clearance as mild (50 to < 80 ml/min), moderate (30 to < 50 ml/min), and severe
(< 30 ml/min), as well as patients with end-stage renal disease (ESRD) on haemodialysis.
Patients with mild renal impairment did not have a clinically meaningful increase in the plasma
concentration of sitagliptin as compared to normal healthy control subjects. An approximately 2-fold
increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment,
and an approximately 4-fold increase was observed in patients with severe renal impairment and in
patients with ESRD on haemodialysis, as compared to normal healthy control subjects. Sitagliptin was
modestly removed by haemodialysis (13.5 % over a 3- to 4-hour haemodialysis session starting
4 hours post-dose). Sitagliptin is not recommended for use in patients with moderate or severe renal
impairment including those with ESRD since experience in these patients is too limited (see
section 4.2).
Hepatic impairment
No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment
(Child-Pugh score ≤ 9). There is no clinical experience in patients with severe hepatic impairment
(Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepatic
impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly
No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the
pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II
data. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of
sitagliptin compared to younger subjects.
Paediatric
No studies with sitagliptin have been performed in paediatric patients.
Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of
Phase I and Phase II data.
Metformin
Absorption
After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg
metformin tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30 %.
15
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1
µg/ml. In controlled clinical trials, maximum metformin plasma levels (C max ) did not exceed 4 µg/ml,
even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration
of a dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC and a 35 min
prolongation of time to peak plasma concentration was observed. The clinical relevance of this
decrease is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower
than the plasma peak and appears at approximately the same time. The red blood cells most likely
represent a secondary compartment of distribution. The mean Vd ranged between 63 – 276 l.
Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of
metformin in plasma.
5.3 Preclinical safety data
No animal studies have been conducted with Velmetia.
In 16-week studies in which dogs were treated with either metformin alone or a combination of
metformin and sitagliptin, no additional toxicity was observed from the combination. The NOEL in
these studies was observed at exposures to sitagliptin of approximately 6 times the human exposure
and to metformin of approximately 2.5 times the human exposure.
The following data are findings in studies performed with sitagliptin or metformin individually.
Sitagliptin
Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-
effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these
findings for humans is unknown. Transient treatment-related physical signs, some of which suggest
neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,
decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately
23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was
also observed histologically at doses resulting in systemic exposure levels of approximately 23 times
the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the
clinical exposure level.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not
carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at
systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to
correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats
was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin
(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation
in humans.
16
No treatment related effects on fertility were observed in male and female rats given sitagliptin prior to
and throughout mating.
In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib
malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels
more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than
29 times the human exposure levels. Because of the high safety margins, these findings do not suggest
a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of
lactating rats (milk/plasma ratio: 4:1).
Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core :
microcrystalline cellulose (E460)
povidone K29/32 (E1201)
sodium lauril sulfate
sodium stearyl fumarate
Film coating :
polyvinyl alcohol
macrogol 3350
talc (E553b)
titanium dioxide (E171)
iron oxide red (E172)
iron oxide black (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months.
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
Opaque blisters (PVC/PE/PVDC and aluminum). Packs of 14, 28, 56, 112, 168, 196 film-coated
tablets, multi-packs containing 196 (2 packs of 98) film-coated tablets. Pack of 50 x 1 film-coated
tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
17
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/08/456/001
EU/1/08/456/002
EU/1/08/456/003
EU/1/08/456/004
EU/1/08/456/005
EU/1/08/456/006
EU/1/08/456/007
EU/1/08/456/015
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16 July 2008
10. DATE OF REVISION OF THE TEXT
Detailed information on this product is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
18
1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/1,000 mg film-coated tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 1,000 mg of metformin
hydrochloride.
For a full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Film-coated tablet (tablet).
Capsule-shaped, red film-coated tablet with “577” debossed on one side.
4.
CLINICAL PARTICULARS
4.1 Therapeutic indications
For patients with type 2 diabetes mellitus:
Velmetia is indicated as an adjunct to diet and exercise to improve glycaemic control in patients
inadequately controlled on their maximal tolerated dose of metformin alone or those already being
treated with the combination of sitagliptin and metformin.
Velmetia is indicated in combination with a sulphonylurea (i.e., triple combination therapy) as an
adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of
metformin and a sulphonylurea.
Velmetia is indicated as triple combination therapy with a peroxisome proliferator-activated receptor
gamma (PPARγ) agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients
inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist.
Velmetia is also indicated as add-on to insulin (i.e., triple combination therapy) as an adjunct to diet
and exercise to improve glycaemic control in patients when stable dose of insulin and metformin alone
do not provide adequate glycaemic control.
4.2 Posology and method of administration
Posology
The dose of antihyperglycaemic therapy with Velmetia should be individualised on the basis of the
patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum
recommended daily dose of 100 mg sitagliptin.
For patients inadequately controlled on maximal tolerated dose of metformin monotherapy
For patients not adequately controlled on metformin alone, the usual starting dose of Velmetia should
provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin
already being taken.
For patients switching from co-administration of sitagliptin and metformin
For patients switching from co-administration of sitagliptin and metformin, Velmetia should be
initiated at the dose of sitagliptin and metformin already being taken.
19
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of
metformin and a sulphonylurea
The dose of Velmetia should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose)
and a dose of metformin similar to the dose already being taken. When Velmetia is used in
combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the
risk of hypoglycaemia (see section 4.4).
For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of
metformin and a PPARγ agonist
The dose of Velmetia should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose)
and a dose of metformin similar to the dose already being taken.
For patients inadequately controlled on dual combination therapy with insulin and the maximal
tolerated dose of metformin
The dose of Velmetia should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose)
and a dose of metformin similar to the dose already being taken. When Velmetia is used in
combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia
(see section 4.4).
For the different doses on metformin, Velmetia is available in strengths of 50 mg sitagliptin and
850 mg metformin hydrochloride or 1,000 mg metformin hydrochloride.
All patients should continue their diet with an adequate distribution of carbohydrate intake during the
day. Overweight patients should continue their energy-restricted diet.
Special populations
Renal impairment
Velmetia should not be used in patients with moderate or severe renal impairment (creatinine
clearance < 60 ml/min) (see sections 4.3 and 4.4).
Hepatic impairment
Velmetia should not be used in patients with hepatic impairment (see sections 4.3 and 5.2).
Elderly
As metformin and sitagliptin are excreted by the kidney, Velmetia should be used with caution as age
increases. Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic
acidosis, particularly in the elderly (see sections 4.3 and 4.4). Limited safety data on sitagliptin is
available in patients > 75 years of age and care should be exercised.
Paediatric population
Velmetia is not recommended for use in children below 18 years of age due to a lack of data on its
safety and efficacy in this population.
Method of administration
Velmetia should be given twice daily with meals to reduce the gastrointestinal undesirable effects
associated with metformin.
4.3 Contraindications
Velmetia is contraindicated in patients with:
-
hypersensitivity to the active substances or to any of the excipients (see sections 4.4 and 4.8);
-
diabetic ketoacidosis, diabetic pre-coma;
-
acute conditions with the potential to alter renal function such as:
-
dehydration,
20
-
moderate and severe renal impairment (creatinine clearance < 60 ml/min) (see section 4.4);
-
severe infection,
-
intravascular administration of iodinated contrast agents (see section 4.4);
-
acute or chronic disease which may cause tissue hypoxia such as:
-
cardiac or respiratory failure,
-
recent myocardial infarction,
-
shock;
-
hepatic impairment;
-
acute alcohol intoxication, alcoholism;
-
lactation.
4.4 Special warnings and precautions for use
General
Velmetia should not be used in patients with type 1 diabetes and must not be used for the treatment of
diabetic ketoacidosis.
Pancreatitis
In post-marketing experience there have been spontaneously reported adverse reactions of acute
pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis:
persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation
of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or
haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Velmetia and
other potentially suspect medicinal products should be discontinued.
Lactic acidosis
Lactic acidosis is a very rare, but serious (high mortality in the absence of prompt treatment),
metabolic complication that can occur due to metformin accumulation. Reported cases of lactic
acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal
failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated
risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake,
hepatic insufficiency and any conditions associated with hypoxia.
Diagnosis
Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by
coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l,
and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, treatment
with the medicinal product should be discontinued and the patient hospitalised immediately (see
section 4.9).
Renal function
Metformin and sitagliptin are known to be substantially excreted by the kidney. Metformin-related
lactic acidosis increases with the degree of impairment of renal function, therefore, serum creatinine
concentrations should be determined regularly:
-
at least once a year in patients with normal renal function
-
at least two to four times a year in patients with serum creatinine levels at or above the upper
limit of normal and in elderly patients.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be
exercised in situations where renal function may become impaired, for example when initiating
antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory
drug (NSAID).
Hypoglycaemia
Patients receiving Velmetia in combination with a sulphonylurea or with insulin may be at risk for
hypoglycaemia. Therefore, a reduction in the dose of the sulphonylurea or insulin may be necessary.
21
-
shock,
Hypersensitivity reactions
Postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have
been reported. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions
including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after
initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a
hypersensitivity reaction is suspected, discontinue Velmetia, assess for other potential causes of the
event, and institute alternative treatment for diabetes (see section 4.8).
Surgery
As Velmetia contains metformin hydrochloride, the treatment should be discontinued 48 hours before
elective surgery with general, spinal or epidural anaesthesia. Velmetia should not usually be resumed
earlier than 48 hours afterwards and only after renal function has been re-evaluated and found to be
normal.
Administration of iodinated contrast agent
The intravascular administration of iodinated contrast agents in radiological studies can lead to renal
failure which has been associated with lactic acidosis in patients receiving metformin. Therefore,
Velmetia should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours
afterwards, and only after renal function has been re-evaluated and found to be normal (see
section 4.5).
Change in clinical status of patients with previously controlled type 2 diabetes
A patient with type 2 diabetes previously well controlled on Velmetia who develops laboratory
abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated
promptly for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes
and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and metformin levels. If
acidosis of either form occurs, Velmetia must be stopped immediately and other appropriate corrective
measures initiated.
4.5 Interaction with other medicinal products and other forms of interaction
Co-administration of multiple doses of sitagliptin (50 mg twice daily) and metformin (1,000 mg twice
daily) did not meaningfully alter the pharmacokinetics of either sitagliptin or metformin in patients
with type 2 diabetes.
Pharmacokinetic drug interaction studies with Velmetia have not been performed; however, such
studies have been conducted with the individual active substances of Velmetia, sitagliptin and
metformin.
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of
fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Velmetia (see
section 4.4). Consumption of alcohol and medicinal products containing alcohol should be avoided.
Cationic agents that are eliminated by renal tubular secretion (e.g., cimetidine) may interact with
metformin by competing for common renal tubular transport systems. A study conducted in seven
normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased
metformin systemic exposure (AUC) by 50 % and C max by 81 %. Therefore, close monitoring of
glycaemic control, dose adjustment within the recommended posology and changes in diabetic
treatment should be considered when cationic agents that are eliminated by renal tubular secretion are
co-administered.
The intravascular administration of iodinated contrast agents in radiological studies may lead to renal
failure, resulting in metformin accumulation and a risk of lactic acidosis. Therefore, Velmetia should
be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and
only after renal function has been re-evaluated and found to be normal (see section 4.4).
22
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic
hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring
performed, especially at the beginning of treatment with such medicinal products. If necessary, the
dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other
medicinal product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dose of the
antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal
product and on its discontinuation.
Effects of other medicinal products on sitagliptin
Clinical data described below suggest that the risk for clinically meaningful interactions following
co-administration of other medicinal products is low.
Ciclosporin: A study was conducted to assess the effect of ciclosporin, a potent inhibitor of
p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose
of sitagliptin and a single 600 mg oral dose of ciclosporin increased the AUC and C max of sitagliptin by
approximately 29 % and 68 %, respectively. These changes in sitagliptin pharmacokinetics were not
considered to be clinically meaningful. The renal clearance of sitagliptin was not meaningfully altered.
Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin
is CYP3A4, with contribution from CYP2C8. In patients with normal renal function, metabolism,
including via CYP3A4, plays only a small role in the clearance of sitagliptin. Metabolism may play a
more significant role in the elimination of sitagliptin in the setting of severe renal impairment or end-
stage renal disease (ESRD). For this reason, it is possible that potent CYP3A4 inhibitors (i.e.,
ketoconazole, itraconazole, ritonavir, clarithromycin) could alter the phamacokinetics of sitagliptin in
patients with severe renal impairment or ESRD. The effects of potent CYP3A4 inhibitors in the setting
of renal impairment has not been assessed in a clinical study.
In vitro transport studies showed that sitagliptin is a substrate for p-glycoprotein and organic anion
transporter-3 (OAT3). OAT3 mediated transport of sitagliptin was inhibited in vitro by probenecid,
although the risk of clinically meaningful interactions is considered to be low. Concomitant
administration of OAT3 inhibitors has not been evaluated in vivo .
Effects of sitagliptin on other medicinal products
In vitro data suggest that sitagliptin does not inhibit nor induce CYP450 isoenzymes. In clinical
studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide,
simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low
propensity for causing interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic
cationic transporter (OCT). Sitagliptin had a small effect on plasma digoxin concentrations, and may
be a mild inhibitor of p-glycoprotein in vivo .
Digoxin : Sitagliptin had a small effect on plasma digoxin concentrations. Following administration of
0.25 mg digoxin concomitantly with 100 mg of sitagliptin daily for 10 days, the plasma AUC of
digoxin was increased on average by 11 %, and the plasma C max on average by 18 %. No dose
adjustment of digoxin is recommended. However, patients at risk of digoxin toxicity should be
monitored for this when sitagliptin and digoxin are administered concomitantly.
4.6 Fertility, pregnancy and lactation
There are no adequate data from the use of sitagliptin in pregnant women. Studies in animals have
shown reproductive toxicity at high doses of sitagliptin (see section 5.3).
A limited amount of data suggest the use of metformin in pregnant women is not associated with an
increased risk of congenital malformations. Animal studies with metformin do not indicate harmful
23
effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal
development (see also section 5.3).
Velmetia should not be used during pregnancy. If a patient wishes to become pregnant or if a
pregnancy occurs, treatment with Velmetia should be discontinued and switched to insulin treatment
as soon as possible.
No studies in lactating animals have been conducted with the combined active substances of Velmetia.
In studies performed with the individual active substances, both sitagliptin and metformin are excreted
in the milk of lactating rats. Metformin is excreted in human milk in small amounts. It is not known
whether sitagliptin is excreted in human milk. Velmetia must therefore not be used in women who are
breast-feeding (see section 4.3).
4.7 Effects on ability to drive and use machines
Velmetia has no known influence on the ability to drive and use machines. However, when driving or
operating machines, it should be taken into account that dizziness and somnolence have been reported
with sitagliptin.
In addition, patients should be alerted to the risk of hypoglycaemia when Velmetia is used in
combination with sulphonylurea agents or with insulin.
4.8 Undesirable effects
There have been no therapeutic clinical trials conducted with Velmetia tablets however bioequivalence
of Velmetia with co-administered sitagliptin and metformin has been demonstrated (see section 5.2).
Sitagliptin and metformin
Adverse reactions considered as drug related reported in excess (> 0.2 % and difference > 1 patient) of
placebo and in patients receiving sitagliptin in combination with metformin in double-blind studies are
listed below as MedDRA preferred term by system organ class and absolute frequency (Table 1).
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon
(≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies
Adverse reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin with
Metformin 1
Sitagliptin with
Metformin and a
Sulphonylurea 2
Sitagliptin with
Metformin and
a PPARγ Agent
(rosiglitazone) 3
Sitagliptin with
Metformin and
Insulin 4
Time-point
24-week
24-week
18-week
24-week
Metabolism and nutrition disorders
hypoglycaemia *
Very common
Common
Very common
Nervous system disorders
headache
Common
Uncommon
somnolence
Uncommon
Gastrointestinal disorders
diarrhoea
Uncommon
Common
nausea
Common
constipation
Common
upper abdominal
pain
Uncommon
24
 
Adverse reaction
Frequency of adverse reaction by treatment regimen
Sitagliptin with
Metformin 1
Sitagliptin with
Metformin and a
Sulphonylurea 2
Sitagliptin with
Metformin and
a PPARγ Agent
(rosiglitazone) 3
Sitagliptin with
Metformin and
Insulin 4
Time-point
24-week
24-week
18-week
24-week
vomiting
Common
dry mouth
Uncommon
General disorders and administration site conditions
peripheral oedema
Common
Investigations
blood glucose
decreased
Uncommon
* In clinical trials of sitagliptin as monotherapy and sitagliptin as part of combination therapy with
metformin or metformin and a PPARγ agent, rates of hypoglycaemia reported with sitagliptin were
similar to rates in patients taking placebo.
Observed in the 54-week analysis.
1
In this placebo-controlled 24-week study of sitagliptin 100 mg once daily added to ongoing
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin added to ongoing metformin compared to treatment with placebo added to ongoing
metformin was 9.3 % and 10.1 %, respectively.
In an additional 1-year study of sitagliptin 100 mg once daily added to ongoing metformin, the
incidence of adverse reactions considered as drug-related in patients treated with sitagliptin added to
ongoing metformin compared to sulphonylurea added to ongoing metformin was 14.5 % and
30.3 %, respectively.
In pooled studies of up to 1 year in duration comparing sitagliptin added to ongoing metformin to a
sulphonylurea agent added to ongoing metformin, adverse reactions considered as drug-related
reported in patients treated with sitagliptin 100 mg occurring in excess (> 0.2 % and difference
> 1 patient) of that in patients receiving the sulphonylurea agent are as follows: anorexia
(Metabolism and nutritional disorders; frequency uncommon) and weight decreased (Investigations;
frequency uncommon).
2
In this 24-week placebo-controlled study of sitagliptin 100 mg once daily added to ongoing
combination treatment with glimepiride and metformin, the overall incidence of adverse reactions
considered as drug-related in patients treated with the addition of sitagliptin to the ongoing treatment
with glimepiride and metformin was 18.1 % compared to treatment with the addition of placebo to
the ongoing treatment with glimepiride and metformin which was 7.1 %.
3
In this study of sitagliptin 100 mg once daily in combination with rosiglitazone and metformin,
which continued through 54 weeks, the incidence of adverse reactions considered as drug-related in
patients treated with sitagliptin combination compared to treatment with the placebo combination
was 15.3 % and 10.9 %, respectively. Other drug-related adverse reactions reported in the 54-week
analysis (frequency common) in patients treated with the sitagliptin combination occurring in excess
(> 0.2 % and difference > 1 patient) of that in patients treated with the placebo combination were:
headache, cough, vomiting, hypoglycaemia, fungal skin infection, and upper respiratory tract
infection.
4
In this 24-week placebo-controlled study of sitagliptin 100 mg once daily as add-on to insulin and
metformin, the incidence of adverse reactions considered as drug-related in patients treated with
sitagliptin in combination with insulin/metformin compared to treatment with placebo in
combination with insulin/metformin was 16.2 % and 9.0 %, respectively.
25
 
In a 24-week study of initial combination therapy with sitagliptin and metformin administered twice
daily (sitagliptin/metformin 50 mg/500 mg or 50 mg/1,000 mg), the overall incidence of adverse
reactions considered as drug-related in patients treated with the combination of sitagliptin and
metformin compared to patients treated with placebo was 14.0 % and 9.7 %, respectively. The overall
incidence of adverse reactions considered as drug-related in patients treated with the combination of
sitagliptin and metformin was comparable to metformin alone (14.0 % each) and greater than
sitagliptin alone (6.7 %), with the differences relative to sitagliptin alone primarily due to
gastrointestinal adverse reactions.
Additional information on the individual active substances of the fixed dose combination
Sitagliptin
In addition, in monotherapy studies of up to 24 weeks in duration of sitagliptin 100 mg once daily
alone compared to placebo, adverse reactions considered as drug-related reported in patients treated
with sitagliptin in excess (> 0.2 % and difference > 1 patient) of that in patients receiving placebo are
headache, hypoglycaemia, constipation, and dizziness.
In addition to the drug related adverse reactions described above, adverse events (reported regardless
of causal relationship to medicinal product) occurring in at least 5 % and more commonly in patients
treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional
adverse events that occurred more frequently in patients treated with sitagliptin (not reaching the 5 %
level, but occurring with an incidence of > 0.5 % higher with sitagliptin than that in the control group)
included osteoarthritis and pain in extremity.
Across clinical studies, a small increase in white blood cell (WBC) count (approximately
200 cells/microl difference in WBC vs placebo; mean baseline WBC approximately
6,600 cells/microl) was observed due to an increase in neutrophils. This observation was seen in most
but not all studies. This change in laboratory parameters is not considered to be clinically relevant.
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed
with sitagliptin treatment.
Post-marketing data
During post-approval use of Velmetia or sitagliptin, one of the active substances of Velmetia,
additional adverse reactions have been reported (frequency not known). These reactions have been
reported when Velmetia or sitagliptin have been used alone and/or in combination with other
antihyperglycaemic agents: hypersensitivity reactions including anaphylaxis, angioedema, rash,
urticaria, cutaneous vasculitis, and exfoliative skin conditions including Stevens-Johnson syndrome
(see section 4.4); acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotizing
pancreatitis (see section 4.4); impaired renal function, including acute renal failure (sometimes
requiring dialysis); vomiting.
Metformin
Clinical Trial Data and Post-marketing data
Table 2 presents adverse reactions by system organ class and by frequency category. Frequency
categories are based on information available from metformin Summary of Product Characteristics
available in the EU.
26
Table 2. The frequency of metformin adverse reactions identified from clinical trial and
postmarketing data
Adverse reaction
Frequency
Metabolism and nutrition disorders
lactic acidosis Very rare
vitamin B12 deficiency a Very rare
Nervous system disorders
metallic taste Common
Gastrointestinal disorders
gastrointestinal symptoms b Very common
Hepatobiliary disorders
liver function disorders, hepatitis Very rare
Skin and subcutaneous tissue disorders
urticaria, erythema, pruritis Very rare
a Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption
which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic
anaemia).
b Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
occur most frequently during initiation of therapy and resolve spontaneously in most cases.
4.9 Overdose
No data are available with regard to overdose of Velmetia.
During controlled clinical trials in healthy subjects, single doses of up to 800 mg sitagliptin were
generally well tolerated. Minimal increases in QTc, not considered to be clinically relevant, were
observed in one study at a dose of 800 mg sitagliptin. There is no experience with doses above 800 mg
in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse
reactions observed with sitagliptin with doses of up to 600 mg per day for periods of up to 10 days and
400 mg per day for periods of up to 28 days.
A large overdose of metformin (or co-existing risks of lactic acidosis) may lead to lactic acidosis
which is a medical emergency and must be treated in hospital. The most effective method to remove
lactate and metformin is haemodialysis.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5 % of the dose was removed
over a 3- to 4-hour haemodialysis session. Prolonged haemodialysis may be considered if clinically
appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove
unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an
electrocardiogram), and institute supportive therapy if required.
27
 
5.
PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicines used in diabetes, Combinations of oral blood glucose lowering
drugs, ATC code: A10BD07
Velmetia combines two antihyperglycaemic agents with complementary mechanisms of action to
improve glycaemic control in patients with type 2 diabetes: sitagliptin phosphate, a dipeptidyl
peptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.
Sitagliptin
Sitagliptin phosphate is an orally-active, potent, and highly selective inhibitor of the dipeptidyl
peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. The DPP-4 inhibitors are a class of
agents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels
of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the
physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or
elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also
lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production.
When blood glucose levels are low, insulin release is not enhanced and glucagon secretion is not
suppressed. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not
inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Sitagliptin differs in
chemical structure and pharmacological action from GLP-1 analogues, insulin, sulphonylureas or
meglitinides, biguanides, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, alpha-
glucosidase inhibitors, and amylin analogues.
In a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations,
whereas metformin alone increased active and total GLP-1 concentrations to similar extents.
Co-administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
Sitagliptin, but not metformin, increased active GIP concentrations.
Overall, sitagliptin improved glycaemic control when used as monotherapy or in combination
treatment.
In clinical trials, sitagliptin as monotherapy improved glycaemic control with significant reductions in
haemoglobin A 1c (HbA 1c ) and fasting and postprandial glucose. Reduction in fasting plasma glucose
(FPG) was observed at 3 weeks, the first time point at which FPG was measured. The observed
incidence of hypoglycaemia in patients treated with sitagliptin was similar to placebo. Body weight
did not increase from baseline with sitagliptin therapy. Improvements in surrogate markers of beta cell
function, including HOMA-β (Homeostasis Model Assessment-β), proinsulin to insulin ratio, and
measures of beta cell responsiveness from the frequently-sampled meal tolerance test were observed.
Studies of sitagliptin in combination with metformin
In a 24-week, placebo-controlled clinical study to evaluate the efficacy and safety of the addition of
sitagliptin 100 mg once daily to ongoing metformin, sitagliptin provided significant improvements in
glycaemic parameters compared with placebo. Change from baseline in body weight was similar for
patients treated with sitagliptin relative to placebo. In this study there was a similar incidence of
hypoglycaemia reported for patients treated with sitagliptin or placebo.
In a 24-week placebo-controlled factorial study of initial therapy, sitagliptin 50 mg twice daily in
combination with metformin (500 mg or 1,000 mg twice daily) provided significant improvements in
glycaemic parameters compared with either monotherapy. The decrease in body weight with the
combination of sitagliptin and metformin was similar to that observed with metformin alone or
placebo; there was no change from baseline for patients on sitagliptin alone. The incidence of
hypoglycaemia was similar across treatment groups.
28
Study of sitagliptin in combination with metformin and a sulphonylurea
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to glimepiride (alone or in combination with metformin). The addition of
sitagliptin to glimepiride and metformin provided significant improvements in glycaemic parameters.
Patients treated with sitagliptin had a modest increase in body weight (+1.1 kg) compared to those
given placebo.
Study of sitagliptin in combination with metformin and a PPARγ agonist
A 54 week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to the combination of rosiglitazone and metformin. The addition of
sitagliptin to rosiglitazone and metformin provided significant improvements in glycaemic parameters
at the primary timepoint of Week 18, with improvements sustained through the end of the study.
Change from baseline in body weight was similar for patients treated with sitagliptin relative to
placebo (1.9 vs. 1.3 kg).
Study of sitagliptin in combination with metformin and insulin
A 24-week placebo-controlled study was designed to evaluate the efficacy and safety of sitagliptin
(100 mg once daily) added to insulin (at a stable dose for at least 10 weeks) with or without metformin
(at least 1,500 mg). In patients taking pre-mixed insulin, the mean daily dose was 70.9 U/day. In
patients taking non-pre-mixed (intermediate/long-acting) insulin, the mean daily dose was 44.3 U/day.
Data from the 73 % of patients who were taking metformin are presented in Table 3. The addition of
sitagliptin to insulin provided significant improvements in glycaemic parameters. There was no
meaningful change from baseline in body weight in either group.
Table 3: HbA 1c results in placebo-controlled combination therapy studies of sitagliptin and
metformin *
Study
Mean baseline
HbA 1c (%)
Mean change from
baseline HbA 1c (%)
Placebo-corrected mean change
in HbA 1c (%)
(95 % CI)
Sitagliptin 100 mg once daily
added to ongoing metformin
therapy
(N=453)
8.0
-0.7
-0.7 †‡
(-0.8, -0.5)
Sitagliptin 100 mg once daily
added to ongoing glimepiride
+ metformin therapy
(N=115)
8.3
-0.6
-0.9 †‡
(-1.1, -0.7)
Sitagliptin 100 mg once daily
added to ongoing
rosiglitazone + metformin
therapy (N=170)
-0.7 †‡
(-0.9, -0.5)
-0.8 †‡
(-1.0, -0.5)
Week 18
8.8
-1.0
Week 54
8.8
-1.0
Sitagliptin 100 mg once daily
added to ongoing insulin +
metformin therapy
(N=223)
8.7
-0.7 §
-0.5 §,‡
(-0.7, -0.4)
Initial Therapy (twice daily) :
Sitagliptin 50 mg +
metformin 500 mg
(N=183)
8.8
-1.4
-1.6 †‡
(-1.8, -1.3)
29
 
Study
Mean baseline
HbA 1c (%)
Mean change from
baseline HbA 1c (%)
Placebo-corrected mean change
in HbA 1c (%)
(95 % CI)
Initial Therapy (twice daily) :
Sitagliptin 50 mg +
metformin 1,000 mg
(N=178)
8.8
-1.9
-2.1 †‡
(-2.3, -1.8)
* All Patients Treated Population (an intention-to-treat analysis).
Least squares means adjusted for prior antihyperglycaemic therapy status and baseline value.
p< 0.001 compared to placebo or placebo + combination treatment.
HbA 1c (%) at week 24.
§ Least squares mean adjusted for insulin use at Visit 1 (pre-mixed vs. non-pre-mixed [intermediate- or long-acting]), and
baseline value.
In a 52-week study, comparing the efficacy and safety of the addition of sitagliptin 100 mg once daily
or glipizide (a sulphonylurea agent) in patients with inadequate glycaemic control on metformin
monotherapy, sitagliptin was similar to glipizide in reducing HbA 1c (-0.7 % mean change from
baselines at week 52, with baseline HbA 1c of approximately 7.5 % in both groups). The mean glipizide
dose used in the comparator group was 10 mg per day with approximately 40 % of patients requiring a
glipizide dose of ≤ 5 mg/day throughout the study. However, more patients in the sitagliptin group
discontinued due to lack of efficacy than in the glipizide group. Patients treated with sitagliptin
exhibited a significant mean decrease from baseline in body weight (-1.5 kg) compared to a significant
weight gain in patients administered glipizide (+1.1 kg). In this study, the proinsulin to insulin ratio, a
marker of efficiency of insulin synthesis and release, improved with sitagliptin and deteriorated with
glipizide treatment. The incidence of hypoglycaemia in the sitagliptin group (4.9 %) was significantly
lower than that in the glipizide group (32.0 %).
Metformin
Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial
plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
Metformin may act via three mechanisms:
-
by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis
-
in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and
utilisation
-
by delaying intestinal glucose absorption
Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin
increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and
GLUT-4).
In humans, independently of its action on glycaemia, metformin has favourable effects on lipid
metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term
clinical studies: metformin reduces total cholesterol, LDLc and triglyceride levels.
The prospective randomised (UKPDS) study has established the long-term benefit of intensive blood
glucose control in type 2 diabetes. Analysis of the results for overweight patients treated with
metformin after failure of diet alone showed:
-
a significant reduction of the absolute risk of any diabetes-related complication in the metformin
group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years),
p=0.0023, and versus the combined sulphonylurea and insulin monotherapy groups
(40.1 events/1,000 patient-years), p=0.0034
-
a significant reduction of the absolute risk of any diabetes-related mortality: metformin
7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 patient-years, p=0.017
-
a significant reduction of the absolute risk of overall mortality: metformin
13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years, (p=0.011),
and versus the combined sulphonylurea and insulin monotherapy groups
18.9 events/1,000 patient-years (p=0.021)
30
 
-
a significant reduction in the absolute risk of myocardial infarction: metformin
11 events/1,000 patient-years, diet alone 18 events/1,000 patient-years, (p=0.01).
The European Medicines Agency has waived the obligation to submit the results of studies with
Velmetia in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 for
information on paediatric use).
5.2 Pharmacokinetic properties
Velmetia
A bioequivalence study in healthy subjects demonstrated that the Velmetia (sitagliptin/metformin
hydrochloride) combination tablets are bioequivalent to co-administration of sitagliptin phosphate and
metformin hydrochloride as individual tablets.
The following statements reflect the pharmacokinetic properties of the individual active substances of
Velmetia.
Sitagliptin
Absorption
Following oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed,
with peak plasma concentrations (median T max ) occurring 1 to 4 hours post-dose, mean plasma AUC of
sitagliptin was 8.52 μM•hr, C max was 950 nM. The absolute bioavailability of sitagliptin is
approximately 87 %. Since co-administration of a high-fat meal with sitagliptin had no effect on the
pharmacokinetics, sitagliptin may be administered with or without food.
Plasma AUC of sitagliptin increased in a dose-proportional manner. Dose-proportionality was not
established for C max and C 24hr (C max increased in a greater than dose-proportional manner and C 24hr
increased in a less than dose-proportional manner).
Distribution
The mean volume of distribution at steady state following a single 100-mg intravenous dose of
sitagliptin to healthy subjects is approximately 198 litres. The fraction of sitagliptin reversibly bound
to plasma proteins is low (38 %).
Biotransformation
Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
Approximately 79 % of sitagliptin is excreted unchanged in the urine.
Following a [ 14 C]sitagliptin oral dose, approximately 16 % of the radioactivity was excreted as
metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to
contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the
primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution
from CYP2C8.
In vitro data showed that sitagliptin is not an inhibitor of CYP isoenzymes CYP3A4, 2C8, 2C9, 2D6,
1A2, 2C19 or 2B6, and is not an inducer of CYP3A4 and CYP1A2.
Elimination
Following administration of an oral [ 14 C]sitagliptin dose to healthy subjects, approximately 100 % of
the administered radioactivity was eliminated in faeces (13 %) or urine (87 %) within one week of
dosing. The apparent terminal t ½ following a 100-mg oral dose of sitagliptin was approximately
12.4 hours. Sitagliptin accumulates only minimally with multiple doses. The renal clearance was
approximately 350 ml/min.
Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion.
Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in
the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not
31
been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in
mediating the renal elimination of sitagliptin. However, ciclosporin, a p-glycoprotein inhibitor, did not
reduce the renal clearance of sitagliptin. Sitagliptin is not a substrate for OCT2 or OAT1 or PEPT1/2
transporters. In vitro , sitagliptin did not inhibit OAT3 (IC50=160 μM) or p-glycoprotein (up to
250 μM) mediated transport at therapeutically relevant plasma concentrations. In a clinical study
sitagliptin had a small effect on plasma digoxin concentrations indicating that sitagliptin may be a mild
inhibitor of p-glycoprotein.
Characteristics in patients
The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with
type 2 diabetes.
Renal impairment
A single-dose, open-label study was conducted to evaluate the pharmacokinetics of a reduced dose of
sitagliptin (50 mg) in patients with varying degrees of chronic renal impairment compared to normal
healthy control subjects. The study included patients with renal impairment classified on the basis of
creatinine clearance as mild (50 to < 80 ml/min), moderate (30 to < 50 ml/min), and severe
(< 30 ml/min), as well as patients with end-stage renal disease (ESRD) on haemodialysis.
Patients with mild renal impairment did not have a clinically meaningful increase in the plasma
concentration of sitagliptin as compared to normal healthy control subjects. An approximately 2-fold
increase in the plasma AUC of sitagliptin was observed in patients with moderate renal impairment,
and an approximately 4-fold increase was observed in patients with severe renal impairment and in
patients with ESRD on haemodialysis, as compared to normal healthy control subjects. Sitagliptin was
modestly removed by haemodialysis (13.5 % over a 3- to 4-hour haemodialysis session starting
4 hours post-dose). Sitagliptin is not recommended for use in patients with moderate or severe renal
impairment including those with ESRD since experience in these patients is too limited (see
section 4.2).
Hepatic impairment
No dose adjustment for sitagliptin is necessary for patients with mild or moderate hepatic impairment
(Child-Pugh score ≤ 9). There is no clinical experience in patients with severe hepatic impairment
(Child-Pugh score > 9). However, because sitagliptin is primarily renally eliminated, severe hepatic
impairment is not expected to affect the pharmacokinetics of sitagliptin.
Elderly
No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the
pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II
data. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of
sitagliptin compared to younger subjects.
Paediatric
No studies with sitagliptin have been performed in paediatric patients.
Other patient characteristics
No dose adjustment is necessary based on gender, race, or body mass index (BMI). These
characteristics had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a
composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of
Phase I and Phase II data.
Metformin
Absorption
After an oral dose of metformin, tmax is reached in 2.5 h. Absolute bioavailability of a 500 mg
metformin tablet is approximately 50-60 % in healthy subjects. After an oral dose, the non-absorbed
fraction recovered in faeces was 20-30 %.
32
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the
pharmacokinetics of metformin absorption is non-linear. At the usual metformin doses and dosing
schedules, steady state plasma concentrations are reached within 24-48 h and are generally less than 1
µg/ml. In controlled clinical trials, maximum metformin plasma levels (C max ) did not exceed 4 µg/ml,
even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin. Following administration
of a dose of 850 mg, a 40 % lower plasma peak concentration, a 25 % decrease in AUC and a 35 min
prolongation of time to peak plasma concentration was observed. The clinical relevance of this
decrease is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower
than the plasma peak and appears at approximately the same time. The red blood cells most likely
represent a secondary compartment of distribution. The mean Vd ranged between 63 – 276 l.
Biotransformation
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is > 400 ml/min, indicating that metformin is eliminated by glomerular
filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is
approximately 6.5 h. When renal function is impaired, renal clearance is decreased in proportion to
that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of
metformin in plasma.
5.3 Preclinical safety data
No animal studies have been conducted with Velmetia.
In 16-week studies in which dogs were treated with either metformin alone or a combination of
metformin and sitagliptin, no additional toxicity was observed from the combination. The NOEL in
these studies was observed at exposures to sitagliptin of approximately 6 times the human exposure
and to metformin of approximately 2.5 times the human exposure.
The following data are findings in studies performed with sitagliptin or metformin individually.
Sitagliptin
Renal and liver toxicity were observed in rodents at systemic exposure values 58 times the human
exposure level, while the no-effect level was found at 19 times the human exposure level. Incisor teeth
abnormalities were observed in rats at exposure levels 67 times the clinical exposure level; the no-
effect level for this finding was 58-fold based on the 14-week rat study. The relevance of these
findings for humans is unknown. Transient treatment-related physical signs, some of which suggest
neural toxicity, such as open-mouth breathing, salivation, white foamy emesis, ataxia, trembling,
decreased activity, and/or hunched posture were observed in dogs at exposure levels approximately
23 times the clinical exposure level. In addition, very slight to slight skeletal muscle degeneration was
also observed histologically at doses resulting in systemic exposure levels of approximately 23 times
the human exposure level. A no-effect level for these findings was found at an exposure 6-fold the
clinical exposure level.
Sitagliptin has not been demonstrated to be genotoxic in preclinical studies. Sitagliptin was not
carcinogenic in mice. In rats, there was an increased incidence of hepatic adenomas and carcinomas at
systemic exposure levels 58 times the human exposure level. Since hepatotoxicity has been shown to
correlate with induction of hepatic neoplasia in rats, this increased incidence of hepatic tumors in rats
was likely secondary to chronic hepatic toxicity at this high dose. Because of the high safety margin
(19-fold at this no-effect level), these neoplastic changes are not considered relevant for the situation
in humans.
33
No treatment related effects on fertility were observed in male and female rats given sitagliptin prior to
and throughout mating.
In a pre-/postnatal development study performed in rats sitagliptin showed no adverse effects.
Reproductive toxicity studies showed a slight treatment-related increased incidence of fetal rib
malformations (absent, hypoplastic and wavy ribs) in the offspring of rats at systemic exposure levels
more than 29 times the human exposure levels. Maternal toxicity was seen in rabbits at more than
29 times the human exposure levels. Because of the high safety margins, these findings do not suggest
a relevant risk for human reproduction. Sitagliptin is secreted in considerable amounts into the milk of
lactating rats (milk/plasma ratio: 4:1).
Metformin
Preclinical data for metformin reveal no special hazard for humans based on conventional studies of
safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction.
6.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core :
microcrystalline cellulose (E460)
povidone K29/32 (E1201)
sodium lauril sulfate
sodium stearyl fumarate
Film coating :
polyvinyl alcohol
macrogol 3350
talc (E553b)
titanium dioxide (E171)
iron oxide red (E172)
iron oxide black (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
24 months.
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
Opaque blisters (PVC/PE/PVDC and aluminum). Packs of 14, 28, 56, 112, 168, 196 film-coated
tablets, multi-packs containing 196 (2 packs of 98) film-coated tablets. Pack of 50 x 1 film-coated
tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
34
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
8.
MARKETING AUTHORISATION NUMBER(S)
EU/1/08/456/008
EU/1/08/456/009
EU/1/08/456/010
EU/1/08/456/011
EU/1/08/456/012
EU/1/08/456/013
EU/1/08/456/014
EU/1/08/456/016
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
16 July 2008
10. DATE OF REVISION OF THE TEXT
Detailed information on this product is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
35
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
36
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Merck Sharp & Dohme BV
Waarderweg 39
2031 BN, Haarlem, Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
THE MARKETING AUTHORISATION HOLDER
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 2.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
37
ANNEX III
LABELLING AND PACKAGE LEAFLET
38
A. LABELLING
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton for Velmetia 50 mg/850 mg film-coated tablets
1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/850 mg film-coated tablets
sitagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 850 mg of metformin
hydrochloride.
3.
LIST OF EXCIPIENTS
4.
PHARMACEUTICAL FORM AND CONTENTS
14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
112 film-coated tablets
168 film-coated tablets
196 film-coated tablets
Multi-pack containing 196 (2 packs of 98) film-coated tablets
50 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
40
 
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/456/001 14 film-coated tablets
EU/1/08/456/002 28 film-coated tablets
EU/1/08/456/003 56 film-coated tablets
EU/1/08/456/004 112 film-coated tablets
EU/1/08/456/005 168 film-coated tablets
EU/1/08/456/006 196 film-coated tablets
EU/1/08/456/007 50 x 1 film-coated tablets
EU/1/08/456/015 196 (2 x 98) film-coated tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Velmetia
50 mg
850 mg
41
 
PARTICULARS TO APPEAR ON THE INTERMEDIATE CARTON
Multi-packs of 196 (2 packs of 98 film-coated tablets) – without blue box - 50 mg/850 mg film-
coated tablets
1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/850 mg film-coated tablets
sitagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 850 mg of metformin
hydrochloride.
3.
LIST OF EXCIPIENTS
4.
PHARMACEUTICAL FORM AND CONTENTS
Component of a multi-pack comprising 2 packs, each containing 98 film-coated tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
42
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/456/015
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
43
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
Blister for Velmetia 50 mg/850 mg film-coated tablets
1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/850 mg tablets
sitagliptin/metformin HCl
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
MSD
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
44
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton for Velmetia 50 mg/1,000 mg film-coated tablets
1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/1,000 mg film-coated tablets
sitagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 1,000 mg of metformin
hydrochloride.
3.
LIST OF EXCIPIENTS
4.
PHARMACEUTICAL FORM AND CONTENTS
14 film-coated tablets
28 film-coated tablets
56 film-coated tablets
112 film-coated tablets
168 film-coated tablets
196 film-coated tablets
Multi-pack containing 196 (2 packs of 98) film-coated tablets
50 x 1 film-coated tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
45
 
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/456/008 14 film-coated tablets
EU/1/08/456/009 28 film-coated tablets
EU/1/08/456/010 56 film-coated tablets
EU/1/08/456/011 112 film-coated tablets
EU/1/08/456/012 168 film-coated tablets
EU/1/08/456/013 196 film-coated tablets
EU/1/08/456/014 50 x 1 film-coated tablets
EU/1/08/456/016 196 (2 x 98) film-coated tablets
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Velmetia
50 mg
1,000 mg
46
 
PARTICULARS TO APPEAR ON THE INTERMEDIATE CARTON
Multi-packs of 196 (2 packs of 98 film-coated tablets) – without bleu box - 50 mg/1,000 mg film-
coated tablets
1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/1,000 mg film-coated tablets
sitagliptin/metformin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 50 mg of sitagliptin (as phosphate monohydrate) and 1,000 mg of metformin
hydrochloride.
3.
LIST OF EXCIPIENTS
4.
PHARMACEUTICAL FORM AND CONTENTS
Component of a multi-pack comprising 2 packs, each containing 98 film-coated tablets.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30°C.
47
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/08/456/016
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
48
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
Blister for Velmetia 50 mg/1,000 mg film-coated tablets
1.
NAME OF THE MEDICINAL PRODUCT
Velmetia 50 mg/1,000 mg tablets
sitagliptin/metformin HCl
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
MSD
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
OTHER
49
 
B. PACKAGE LEAFLET
50
PACKAGE LEAFLET: INFORMATION FOR THE USER
Velmetia 50 mg/850 mg film-coated tablets
sitagliptin/metformin hydrochloride
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet :
1.
What Velmetia is and what it is used for
2.
Before you take Velmetia
3.
How to take Velmetia
5.
How to store Velmetia
6.
Further information
1.
WHAT VELMETIA IS AND WHAT IT IS USED FOR
The name of your tablet is Velmetia. It contains two different medicines called sitagliptin and
metformin.
sitagliptin belongs to a class of medicines called DPP-4 inhibitors (dipeptidyl
peptidase-4 inhibitors)
metformin belongs to a class of medicines called biguanides.
They work together to control blood sugar levels in patients with a form of diabetes called ‘type 2
diabetes mellitus’. Velmetia helps to improve the levels of insulin after a meal and lowers the amount
of sugar made by your body.
Along with diet and exercise, this medicine helps lower your blood sugar. Velmetia can be used alone
or with certain other medicines for diabetes (insulin, sulphonylureas, or glitazones).
What is type 2 diabetes?
Type 2 diabetes is also called non-insulin-dependent diabetes mellitus, or NIDDM. Type 2 diabetes is
a condition in which your body does not make enough insulin, and the insulin that your body produces
does not work as well as it should. Your body can also make too much sugar. When this happens,
sugar (glucose) builds up in the blood. This can lead to serious medical problems like heart disease,
kidney disease, blindness, and amputation.
2.
BEFORE YOU TAKE VELMETIA
Do not take Velmetia:
-
if you are allergic (hypersensitive) to sitagliptin or metformin or any of the other ingredients of
Velmetia (listed in section 6)
-
if you have diabetic ketoacidosis (a complication of diabetes with rapid weight loss, nausea or
vomiting) or have had a diabetic coma
-
if you have a severe infection or are dehydrated
-
if you are going to have an X-ray where you will be injected with a dye. You will need to stop
taking Velmetia at the time of the X-ray and for a few days after
51
4.
Possible side effects
-
if you have problems with your kidneys
-
if you have recently had a heart attack or have severe circulatory problems, such as ‘shock’ or
breathing difficulties
-
if you have liver problems
-
if you drink alcohol to excess (either every day or only from time to time)
-
if you are breast-feeding
Do not take Velmetia if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before taking Velmetia.
Take special care with Velmetia
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving Velmetia.
Pancreatitis can be a serious, potentially life-threatening medical condition. Stop taking Velmetia and
call your doctor if you experience severe and persistent stomach pain, with or without vomiting,
because you could have pancreatitis.
Check with your doctor or pharmacist before taking your medicine:
-
if you have or had pancreatitis, gallstones, alcoholism or very high triglycerides. These medical
conditions can increase your chance of getting pancreatitis, or getting it again.
-
if you experience some of the following symptoms: feeling cold or uncomfortable, severe
nausea or vomiting, abdominal pain, unexplained weight loss, muscular cramps, or rapid
breathing. Metformin hydrochloride, one of the ingredients in Velmetia, can cause a rare but
serious side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause
death. Lactic acidosis is a medical emergency and must be treated in a hospital. If you
experience some of the symptoms of lactic acidosis stop taking Velmetia and consult a doctor
immediately
-
During treatment with Velmetia, your doctor will check your kidney function at least once a
year and more frequently if you are elderly or if your kidney function is borderline or at risk of
worsening
-
if you have or have had an allergic reaction to sitagliptin, metformin, or Velmetia
-
if you are taking a sulphonylurea or insulin, diabetes medicines, together with Velmetia, as you
may experience low blood sugar levels (hypoglycaemia). Your doctor may reduce the dose of
your sulphonylurea or insulin
-
if you are going to have an operation under general, spinal or epidural anaesthetic. You may
need to stop taking Velmetia for a couple of days before and after the procedure
-
if you are under 18 years of age
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking
Velmetia.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines obtained without a prescription, including herbal medicines.
The following medicines are particularly important:
medicines used to treat diseases that involve inflammation, like asthma and arthritis
(corticosteroids)
specific medicines for the treatment of high blood pressure (ACE inhibitors)
medicines which increase urine production (diuretics)
specific medicines for the treatment of bronchial asthma (β-sympathomimetics)
iodinated contrast agents or alcohol-containing medicines.
Taking Velmetia with food and drink
Take Velmetia with meals to lower your chance of an upset stomach.
52
-
if you have type 1 diabetes. This is sometimes called insulin-dependent diabetes
Pregnancy and breast-feeding
Women who are pregnant or plan to become pregnant should talk to their doctor before taking
Velmetia. You should not use Velmetia during pregnancy.
Metformin passes into human milk in small amounts. It is not known whether sitagliptin passes into
human milk. It is not known if Velmetia passes into human breast milk. You must not use Velmetia if
you are breast-feeding or plan to breast-feed.
Driving and using machines
Velmetia has no known influence on the ability to drive and use machines. However, when driving or
operating machinery, it should be taken into account that dizziness and drowsiness have been reported
with sitagliptin.
Taking Velmetia in combination with medicines called sulphonylureas or with insulin can cause
hypoglycaemia, which may affect your ability to drive and use machines or work without safe
foothold.
3.
HOW TO TAKE VELMETIA
Always take Velmetia exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Velmetia should be taken:
twice daily by mouth
with meals to lower your chance of an upset stomach.
Your doctor may need to increase your dose to control your blood sugar.
Continue to take Velmetia as long as your doctor prescribes it so you can continue to help
control your blood sugar.
You should continue your diet during treatment with Velmetia and take care that your carbohydrate
intake is equally distributed over the day. If you are overweight continue your energy-restricted diet as
instructed.
Velmetia alone is unlikely to cause abnormally low blood sugar (hypoglycaemia). When Velmetia is
used with a sulphonylurea medicine or with insulin, low blood sugar can occur and your doctor may
reduce the dose of your sulphonylurea or insulin.
Sometimes you may need to stop taking your medicine for a short time. Talk to your doctor for
instructions if you:
have a condition that may be associated with dehydration (large loss of body fluids) such as
being sick with severe vomiting, diarrhoea or fever, or if you drink fluids a lot less than normal
plan to have surgery
are due to get an injection of dye or contrast agent as part of an X-ray
If you take more Velmetia than you should
If you take more than the prescribed dosage of Velmetia, contact your doctor immediately.
If you forget to take Velmetia
If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your
next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose of
Velmetia.
53
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Velmetia may cause side effects, although not everybody gets them.
Very rarely patients taking metformin (one of the active substances of Velmetia) have experienced a
serious condition called lactic acidosis (too much lactic acid in your blood). This is more common in
people whose kidneys are not working properly. Stop taking Velmetia and see a doctor straight away
if you notice any of the following symptoms:
feeling sick (nausea) or being sick (vomiting), abdominal pain, muscular cramps, unexplained
weight loss, rapid breathing, and feeling cold or uncomfortable.
Very common side effects (likely to occur in more than 1 per 10 patients).
Common side effects (likely to occur in less than 1 per 10 but more than 1 per 100 patients).
Uncommon side effects (likely to occur in less than 1 per 100 but more than 1 per 1,000 patients).
Rare side effects (likely to occur in less than 1 per 1,000 but more than 1 per 10,000).
Very rare side effects (likely to occur in less than 1 per 10,000).
Some patients taking metformin have experienced the following side effects after starting sitagliptin:
Common: nausea
Uncommon: weight loss, loss of appetite, abdominal pain, diarrhoea, low blood sugar, drowsiness
Some patients have experienced stomach discomfort when starting the combination of sitagliptin and
metformin together.
Some patients have experienced the following side effects while taking Velmetia with a
sulphonylurea:
Very common: low blood sugar
Common: constipation
Some patients have experienced the following side effects while taking Velmetia in combination with
rosiglitazone:
Common: headache, cough, diarrhoea, vomiting, low blood sugar, fungal skin infection, upper
respiratory infection, swelling of the hands or legs.
Some patients have experienced the following side effects while taking Velmetia in combination with
insulin:
Very common: low blood sugar
Uncommon: dry mouth, headache
Some patients have experienced the following side effects while taking sitagliptin alone:
Common: low blood sugar, headache
Uncommon: dizziness, constipation
In addition, some patients have reported the following side effects while taking sitagliptin:
Common: upper respiratory infection, stuffy or runny nose and sore throat, osteoarthritis, arm or leg
pain.
During post-approval use with Velmetia or sitagliptin, one of the medicines in Velmetia, additional
side effects have also been reported (frequency not known). These side effects have been reported
when Velmetia or sitagliptin have been used alone and/or as part of combination therapy: allergic
reactions, which may be serious, including rash, hives, and swelling of the face, lips, tongue, and
throat that may cause difficulty in breathing or swallowing. If you have an allergic reaction, stop
taking Velmetia and call your doctor right away. Your doctor may prescribe a medicine to treat your
54
allergic reaction and a different medicine for your diabetes. Other side effects that have been reported
include: inflammation of the pancreas; kidney problems (sometimes requiring dialysis); vomiting.
Some patients have experienced the following side effects while taking metformin alone:
Very common: nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
Common: a metallic taste
Very rare: decreased vitamin B12 levels, hepatitis (a problem with your liver), redness of the skin
(rash) or itching, lactic acidosis (excess of lactic acid in your blood) particularly in patients whose
kidneys are not working properly. The symptoms include feeling cold or uncomfortable, severe nausea
or vomiting, abdominal pain, unexplained weight loss, or rapid breathing
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE VELMETIA
Keep out of the reach and sight of children.
Do not use Velmetia after the expiry date which is stated on the blister and the carton. The expiry date
refers to the last day of the month.
Do not store above 30°C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Velmetia contains
-
The active substances are sitagliptin and metformin. Each film-coated tablet contains 50 mg of
sitagliptin (as phosphate monohydrate) and 850 mg of metformin hydrochloride.
-
The other ingredients are: microcrystalline cellulose (E460), povidone K 29/32 (E1201), sodium
lauril sulfate, and sodium stearyl fumarate. In addition, the film coating contains the following
inactive ingredients: polyvinyl alcohol, macrogol 3350, talc (E553b), titanium dioxide (E171),
iron oxide red (E172), and iron oxide black (E172).
What Velmetia looks like and contents of the pack
Capsule-shaped, pink film-coated tablet with “515” debossed on one side.
Opaque blisters (PVC/PE/PVDC and aluminum). Packs of 14, 28, 56, 112, 168, 196 film-coated
tablets, multi-packs containing 196 (2 packs of 98) film-coated tablets. Pack of 50 x 1 film-coated
tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
Manufacturer
Merck Sharp & Dohme BV
Waarderweg 39
2031 BN, Haarlem, Netherlands
55
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 386 93
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 386 93
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
EGIS Gyógyszergyár NyRT
Tel.: + 36 1 265 55 55
mailbox@egis.hu
Česká republika
Merck Sharp & Dohme IDEA , Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
Ċipru
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: 0800 99 99 000
medicalinfo.nl@merck.com
Deutschland
BERLIN-CHEMIE AG
Tel: +49 (0) 30 67070
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Ferrer Internacional, S.A.
Tel: +34 93 600 37 00
medicaldep@ferrergrupo.com
Portugal
LABORATÓRIO MEDINFAR,
Produtos, Farmacêuticos, SA
Tel: +351 800204661
medinfar@medinfar.pt
France
Pierre Fabre Médicament
Tél: +33 (0) 1 49 10 80 00
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
56
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Istituto Gentili S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
Orion Oyj
Puh./Tel: +358 10 4261
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus_info@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 14 00
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 7364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel. +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
57
PACKAGE LEAFLET: INFORMATION FOR THE USER
Velmetia 50 mg/1,000 mg film-coated tablets
sitagliptin/metformin hydrochloride
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet :
1.
What Velmetia is and what it is used for
2.
Before you take Velmetia
3.
How to take Velmetia
5.
How to store Velmetia
6.
Further information
1.
WHAT VELMETIA IS AND WHAT IT IS USED FOR
The name of your tablet is Velmetia. It contains two different medicines called sitagliptin and
metformin.
sitagliptin belongs to a class of medicines called DPP-4 inhibitors (dipeptidyl
peptidase-4 inhibitors)
metformin belongs to a class of medicines called biguanides.
They work together to control blood sugar levels in patients with a form of diabetes called ‘type 2
diabetes mellitus’. Velmetia helps to improve the levels of insulin after a meal and lowers the amount
of sugar made by your body.
Along with diet and exercise, this medicine helps lower your blood sugar. Velmetia can be used alone
or with certain other medicines for diabetes (insulin, sulphonylureas, or glitazones).
What is type 2 diabetes?
Type 2 diabetes is also called non-insulin-dependent diabetes mellitus, or NIDDM. Type 2 diabetes is
a condition in which your body does not make enough insulin, and the insulin that your body produces
does not work as well as it should. Your body can also make too much sugar. When this happens,
sugar (glucose) builds up in the blood. This can lead to serious medical problems like heart disease,
kidney disease, blindness, and amputation.
2.
BEFORE YOU TAKE VELMETIA
Do not take Velmetia:
-
if you are allergic (hypersensitive) to sitagliptin or metformin or any of the other ingredients of
Velmetia (listed in section 6)
-
if you have diabetic ketoacidosis (a complication of diabetes with rapid weight loss, nausea or
vomiting) or have had a diabetic coma
-
if you have a severe infection or are dehydrated
-
if you are going to have an X-ray where you will be injected with a dye. You will need to stop
taking Velmetia at the time of the X-ray and for a few days after
58
4.
Possible side effects
-
if you have problems with your kidneys
-
if you have recently had a heart attack or have severe circulatory problems, such as ‘shock’ or
breathing difficulties
-
if you have liver problems
-
if you drink alcohol to excess (either every day or only from time to time)
-
if you are breast-feeding
Do not take Velmetia if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before taking Velmetia.
Take special care with Velmetia
Cases of inflammation of the pancreas (pancreatitis) have been reported in patients receiving Velmetia.
Pancreatitis can be a serious, potentially life-threatening medical condition. Stop taking Velmetia and
call your doctor if you experience severe and persistent stomach pain, with or without vomiting,
because you could have pancreatitis.
Check with your doctor or pharmacist before taking your medicine:
-
if you have or had pancreatitis, gallstones, alcoholism or very high triglycerides. These medical
conditions can increase your chance of getting pancreatitis, or getting it again.
-
if you experience some of the following symptoms: feeling cold or uncomfortable, severe
nausea or vomiting, abdominal pain, unexplained weight loss, muscular cramps, or rapid
breathing. Metformin hydrochloride, one of the ingredients in Velmetia, can cause a rare but
serious side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause
death. Lactic acidosis is a medical emergency and must be treated in a hospital. If you
experience some of the symptoms of lactic acidosis stop taking Velmetia and consult a doctor
immediately
-
During treatment with Velmetia, your doctor will check your kidney function at least once a
year and more frequently if you are elderly or if your kidney function is borderline or at risk of
worsening
-
if you have or have had an allergic reaction to sitagliptin, metformin, or Velmetia
-
if you are taking a sulphonylurea or insulin, diabetes medicines, together with Velmetia, as you
may experience low blood sugar levels (hypoglycaemia). Your doctor may reduce the dose of
your sulphonylurea or insulin
-
if you are going to have an operation under general, spinal or epidural anaesthetic. You may
need to stop taking Velmetia for a couple of days before and after the procedure
-
if you are under 18 years of age
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking
Velmetia.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines obtained without a prescription, including herbal medicines.
The following medicines are particularly important:
medicines used to treat diseases that involve inflammation, like asthma and arthritis
(corticosteroids)
specific medicines for the treatment of high blood pressure (ACE inhibitors)
medicines which increase urine production (diuretics)
specific medicines for the treatment of bronchial asthma (β-sympathomimetics)
iodinated contrast agents or alcohol-containing medicines.
Taking Velmetia with food and drink
Take Velmetia with meals to lower your chance of an upset stomach.
59
-
if you have type 1 diabetes. This is sometimes called insulin-dependent diabetes
Pregnancy and breast-feeding
Women who are pregnant or plan to become pregnant should talk to their doctor before taking
Velmetia. You should not use Velmetia during pregnancy.
Metformin passes into human milk in small amounts. It is not known whether sitagliptin passes into
human milk. It is not known if Velmetia passes into human breast milk. You must not use Velmetia if
you are breast-feeding or plan to breast-feed.
Driving and using machines
Velmetia has no known influence on the ability to drive and use machines. However, when driving or
operating machinery, it should be taken into account that dizziness and drowsiness have been reported
with sitagliptin.
Taking Velmetia in combination with medicines called sulphonylureas or with insulin can cause
hypoglycaemia, which may affect your ability to drive and use machines or work without safe
foothold.
3.
HOW TO TAKE VELMETIA
Always take Velmetia exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
Velmetia should be taken:
twice daily by mouth
with meals to lower your chance of an upset stomach.
Your doctor may need to increase your dose to control your blood sugar.
Continue to take Velmetia as long as your doctor prescribes it so you can continue to help
control your blood sugar.
You should continue your diet during treatment with Velmetia and take care that your carbohydrate
intake is equally distributed over the day. If you are overweight continue your energy-restricted diet as
instructed.
Velmetia alone is unlikely to cause abnormally low blood sugar (hypoglycaemia). When Velmetia is
used with a sulphonylurea medicine or with insulin, low blood sugar can occur and your doctor may
reduce the dose of your sulphonylurea or insulin.
Sometimes you may need to stop taking your medicine for a short time. Talk to your doctor for
instructions if you:
have a condition that may be associated with dehydration (large loss of body fluids) such as
being sick with severe vomiting, diarrhoea or fever, or if you drink fluids a lot less than normal
plan to have surgery
are due to get an injection of dye or contrast agent as part of an X-ray
If you take more Velmetia than you should
If you take more than the prescribed dosage of Velmetia, contact your doctor immediately.
If you forget to take Velmetia
If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your
next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose of
Velmetia.
60
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Velmetia may cause side effects, although not everybody gets them.
Very rarely patients taking metformin (one of the active substances of Velmetia) have experienced a
serious condition called lactic acidosis (too much lactic acid in your blood). This is more common in
people whose kidneys are not working properly. Stop taking Velmetia and see a doctor straight away
if you notice any of the following symptoms:
feeling sick (nausea) or being sick (vomiting), abdominal pain, muscular cramps, unexplained
weight loss, rapid breathing, and feeling cold or uncomfortable.
Very common side effects (likely to occur in more than 1 per 10 patients).
Common side effects (likely to occur in less than 1 per 10 but more than 1 per 100 patients).
Uncommon side effects (likely to occur in less than 1 per 100 but more than 1 per 1,000 patients).
Rare side effects (likely to occur in less than 1 per 1,000 but more than 1 per 10,000).
Very rare side effects (likely to occur in less than 1 per 10,000).
Some patients taking metformin have experienced the following side effects after starting sitagliptin:
Common: nausea
Uncommon: weight loss, loss of appetite, abdominal pain, diarrhoea, low blood sugar, drowsiness
Some patients have experienced stomach discomfort when starting the combination of sitagliptin and
metformin together.
Some patients have experienced the following side effects while taking Velmetia with a
sulphonylurea:
Very common: low blood sugar
Common: constipation
Some patients have experienced the following side effects while taking Velmetia in combination with
rosiglitazone:
Common: headache, cough, diarrhoea, vomiting, low blood sugar, fungal skin infection, upper
respiratory infection, swelling of the hands or legs.
Some patients have experienced the following side effects while taking Velmetia in combination with
insulin:
Very common: low blood sugar
Uncommon: dry mouth, headache
Some patients have experienced the following side effects while taking sitagliptin alone:
Common: low blood sugar, headache
Uncommon: dizziness, constipation
In addition, some patients have reported the following side effects while taking sitagliptin:
Common: upper respiratory infection, stuffy or runny nose and sore throat, osteoarthritis, arm or leg
pain.
During post-approval use with Velmetia or sitagliptin, one of the medicines in Velmetia, additional
side effects have also been reported (frequency not known). These side effects have been reported
when Velmetia or sitagliptin have been used alone and/or as part of combination therapy: allergic
reactions, which may be serious, including rash, hives, and swelling of the face, lips, tongue, and
throat that may cause difficulty in breathing or swallowing. If you have an allergic reaction, stop
taking Velmetia and call your doctor right away. Your doctor may prescribe a medicine to treat your
61
allergic reaction and a different medicine for your diabetes. Other side effects that have been reported
include: inflammation of the pancreas; kidney problems (sometimes requiring dialysis); vomiting.
Some patients have experienced the following side effects while taking metformin alone:
Very common: nausea, vomiting, diarrhoea, abdominal pain and loss of appetite
Common: a metallic taste
Very rare: decreased vitamin B12 levels, hepatitis (a problem with your liver), redness of the skin
(rash) or itching, lactic acidosis (excess of lactic acid in your blood) particularly in patients whose
kidneys are not working properly. The symptoms include feeling cold or uncomfortable, severe nausea
or vomiting, abdominal pain, unexplained weight loss, or rapid breathing
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE VELMETIA
Keep out of the reach and sight of children.
Do not use Velmetia after the expiry date which is stated on the blister and the carton. The expiry date
refers to the last day of the month.
Do not store above 30°C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Velmetia contains
-
The active substances are sitagliptin and metformin. Each film-coated tablet contains 50 mg of
sitagliptin (as phosphate monohydrate) and 1,000 mg of metformin hydrochloride.
-
The other ingredients are: microcrystalline cellulose (E460), povidone K 29/32 (E1201), sodium
lauril sulfate, and sodium stearyl fumarate. In addition, the film coating contains the following
inactive ingredients: polyvinyl alcohol, macrogol 3350, talc (E553b), titanium dioxide (E171),
iron oxide red (E172), and iron oxide black (E172).
What Velmetia looks like and contents of the pack
Capsule-shaped, red film-coated tablet with “577” debossed on one side.
Opaque blisters (PVC/PE/PVDC and aluminum). Packs of 14, 28, 56, 112, 168, 196 ilm-coated
tablets, multi-packs containing 196 (2 packs of 98) film-coated tablets. Pack of 50 x 1 film-coated
tablets in perforated unit dose blisters.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Merck Sharp & Dohme Ltd.
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom
Manufacturer
Merck Sharp & Dohme BV
Waarderweg 39
2031 BN, Haarlem, Netherlands
62
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Merck Sharp & Dohme B.V.
Succursale belge/Belgisch bijhuis
Tél/Tel: +32 (0) 800 386 93
MSDBelgium_info@merck.com
Luxembourg/Luxemburg
Merck Sharp & Dohme B.V.
Succursale belge
Tél: +32 (0) 800 386 93
MSDBelgium_info@merck.com
България
Мерк Шарп и Доум България ЕООД
Тел.: +359 2 819 3740
info-msdbg@merck.com
Magyarország
EGIS Gyógyszergyár NyRT
Tel.: + 36 1 265 55 55
mailbox@egis.hu
Česká republika
Merck Sharp & Dohme IDEA , Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com
Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com
Ċipru
Danmark
Merck Sharp & Dohme
Tlf: +45 43 28 77 66
dkmail@merck.com
Nederland
Merck Sharp & Dohme BV
Tel: 0800 99 99 000
medicalinfo.nl@merck.com
Deutschland
BERLIN-CHEMIE AG
Tel: +49 (0) 30 67070
Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no
Eesti
Merck Sharp & Dohme OÜ
Tel.: +372 613 9750
msdeesti@merck.com
Österreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com
Eλλάδα
BIANEΞ Α.Ε
Τηλ: +3 0210 80091 11
Mailbox@vianex.gr
Polska
MSD Polska Sp. z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com
España
Ferrer Internacional, S.A.
Tel: +34 93 600 37 00
medicaldep@ferrergrupo.com
Portugal
LABORATÓRIO MEDINFAR,
Produtos, Farmacêuticos, SA
Tel: +351 800204661
medinfar@medinfar.pt
France
Pierre Fabre Médicament
Tél: +33 (0) 1 49 10 80 00
România
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com
63
Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com
Slovenija
Merck Sharp & Dohme, inovativna zdravila d.o.o.
Tel: + 386 1 5204201
msd_slovenia@merck.com
Ísland
Icepharma hf.
Sími: +354 540 8000
ISmail@merck.com
Slovenská republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com
Ιtalia
Istituto Gentili S.p.A.
Tel: +39 06 361911
doccen@merck.com
Suomi/Finland
Orion Oyj
Puh./Tel: +358 10 4261
Κύπρος
Merck Sharp & Dohme Cyprus Limited
Τηλ: +357 22866700
cyprus_info@merck.com
Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 14 00
medicinskinfo@merck.com
Latvija
SIA “Merck Sharp & Dohme Latvija”
Tel: +371 7364 224
msd_lv@merck.com
United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com
Lietuva
UAB “Merck Sharp & Dohme”
Tel. +370 5 278 02 47
msd_lietuva@merck.com
This leaflet was last approved in {MM/YYYY}.
Detailed information on this medicine is available on the website of the European Medicines Agency
web site: http://www.ema.europa.eu/.
64


Source: European Medicines Agency



- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.



http://www.theodora.com/drugs/eu/velmetia.html

Copyright © 1995-2011 ITA all rights reserved.